Myocardial perfusion depends on coronary
artery blood flow, using conductance vessels as epicardial coronary trunks,
resistance vessels as coronary perforants, arterioles and capillaries. Blood
volume is distributed all through myocardial wall, but is mostly present at
subendocardial area, filled by approximately 80% of myocardial blood volume.

Myocardial flow studies were performed
longly in research scenarios in the last 2 decades, almost always using radioactive
microspheres, as intravascular tracers. Those animals' studies allowed an extensive
knowledge of coronary flow dynamics, but in controlled conditions and research
situations.

It was not possible to use any intravascular
tracer in clinical scenarios to understand pathologic findings during ischemic
events. Moreover, data about coronary blood flow were extrapolated from those
animals' experiences, to human physiology, with absence of strong evidences
that those concepts could be wrong in the clinical field.

Recently after a long period of research,
new generations of industrially and hand made designs of ultrasound contrast
agents appear.

Gas containing microbubbles, stables
enough to achieve persistence injected in human circulation, and sized to cross
human capillaries, was developed with different formulas. Some of them, have
a similar rheology as blood red cells, when mixed by intravenous injection,
with human blood pool.

Ultrasound contrast agents were designed
to create gas liquid interfaces to increase the reflectivity of ultrasound.
But, contrast microbubbles are strongly reactive to ultrasound energy, with
intense response to positive and negative pressures when insonificated.

During
the period of positive pressure, bubbles are compressed reducing their size,
and on the other hand, at time of negative pressure bubbles dilate by rarefaction
increasing radius more than they change during time of compression. (Figure
1)

Figure 1

Using
frequencies as those, which are useful in clinical diagnosis, those bubbles
resonate producing non-linear responses, allowing echo machines to detect harmonic
frequencies, (Figure
2) as well as to destroy microbubbles using ultrasound insonification
by manipulation of levels of energy.

Figure 2

Those properties are a powerful tool
to manage bubbles dynamic and persistence in blood pool, fact that associated
with well-known microbubbles rheology, becomes the key to manipulate an intravascular
tracer to understand aspects about red blood cells dynamics, in a clinical scenario.

Ultrasound
technology, developed so fast in the last years, produced 2 trends of software
programs based on 2 different concepts: 1- To use of high levels of ultrasound
energy to destroy ultrasound contrast agents' microbubbles, inducing high level
of harmonics response and simultaneously cleaning up the myocardial capillary
field in the area where ultrasound beam insonificates myocardial microcirculation
(Figure
3) and 2- To use very low energy levels, as low as possible to avoid
bubbles destruction, but producing microbubbles resonance, inducing low levels
of harmonic responses from tissue, but with enough bubbles resonation to be
detected by a high sensitive Doppler mode as Power Doppler harmonics.

Figure 3

Different
manufacturers developed different approaches; all of them designed to minimize
wall motion artifacts and tissue harmonic production, using a type of real time
background subtraction and not any destruction of circulating microbubbles.
(Power pulse inversion, Power modulation, etc.) (Figure
4- 5)

Figure 4

Figure 5

Both techniques demonstrate amazing results
during last 3 years, allowing depicting important issues about myocardial blood
flow, which became the background to interpretive clinical results in different
applications.

Most data were published about myocardial
flow dynamics using ultrasound contrast agents, and also different protocols
were developed in clinical research, both at rest and during stress, to prove
usefulness of myocardial perfusion studies by contrast echocardiography.

There were few papers, conducted by
well-known investigators, showing very bad results in comparison with coronary
angiography and nuclear perfusion studies. Those protocols were performed regardless
knowledge and training of the laboratories participating in terms of contrast
agents applications, and also using old and new software to look at myocardial
perfusion. Those defects in protocol design were probably the explanation of
poor results obtained, and also the pessimistic atmosphere generated around
contrast echocardiography in the field of myocardial perfusion study.

Contrast agents improvement was faster
than technology improvement. This reality acts against a coordinated grow up
of the clinical applications of these state of the art echo techniques.

On the other hand, there are not yet
any intravascular tracers, to be applicated in clinical field. Then it is not
possible to use a GOLD STANDARD for comparison in clinical trials.

It is well known there are deep differences
between anatomic diagnosis (coronary disease diagnosticated by coronary angiography)
and functional studies (exercise or pharmacologic stress) using nuclear medicine
or conventional stress echocardiography, nevertheless correlation between those
methods are significant.

Diagnosis of perfusion defects using
the clinical gold standard, Thallium or sesta MIBI exercise or vasodilators
stress SPECT, are worldwide accepted as the primary clinical tool, for decision
making in patients with coronary artery disease.

Although radioisotopes used for clinical
diagnosis are known to have not an intravascular dynamic and beside they depends
on cellular integrity and metabolic function for caption, they were selected
as a gold standard for myocardial perfusion clinical studies. Most publications
about these topics also compared with quantitative coronary angiography, an
all of them showed a high degree of correlation for diagnosis of induced or
rest perfusion defects and coronary obstruction.

Few
different types of stress, including exercise, inotropics and vasodilators were
included in clinical protocols.
Destructive technique, triggered intermittent harmonic studies, has demonstrated
an enormous impact in clinical diagnosis of perfusion defects adding a great
value over the information from wall motion analysis. This is a key topic because
additional information using perfusion data increases sensitivity in coronary
artery disease diagnosis, without loss of specificity that highly improves test
accuracy. (Figure
6-
7)

Figure 6

Figure 7

What is the limitation for a wide application
of echocardiography to study myocardial perfusion?

1- It is mandatory to understand physical basis about
microbubbles physics and dynamics
2- Education should be planned to train technicians and physicians in new
software and contrast agents' manipulation and characteristics
3- Echocardiography should be performed by well training groups of physicians
or by technicians with close collaboration of medical staff
4- Multicenter protocols performed by worldwide echo laboratories, well trained
in contrast studies and with tight study protocols should be performed after
consensus meetings
5- The protocols approved by consensus have to be applied on different pathologies
and should be check in controlled follow up studies to demonstrate the impact
of use of this technique in health care and health economy
6- Contrast agents and Ultrasound Manufacturers should meet efforts to go
ahead, contributing in education and financial aspects of about described
issues
7- FDA or local countries similar institution regulations should be quickly
accepted, using research potential all around the world specially in countries
where physicians are directly involved in echo studies performance.

All those topics above are not so far
in the horizon to be afraid about the future and present of these techniques.
Focus group meeting showed not difficulties to share experience and coordinated
efforts to achieve those issues. Financial aspects seem to be the big deal at
the present time.

It is important to keep in mind that
nevertheless other images techniques are growing up quickly, in the field of
myocardial perfusion; echocardiography is a world wide accepted diagnostic tool
with real time images and presence anywhere in hospitals and medical offices
with relatively low costs.

Acute coronary syndromes, stress echocardiography
using adenosine or dipyridamole vasodilator stress, as well as dobutamine studies
are ready to go in clinical practice if are used by well-trained medical groups.

Exercise stress echocardiography is
going to be ready quickly with the improvement of software to increase frame
rate in non-destructive technique studies.

Value of myocardial blood volume and
flow quantification will be prove in the near future with the standardization
of protocols, opening a big new window for knowledge about ischemic cardiomyopathy
and coronary artery disease.

Moreover to recognize non reflow phenomenon
easily bedside in real time becomes a tool for viability studies, and triggered
destructive techniques has already prove value of refilling of capillaries in
long trigger intervals to recognize easily viable myocardium.

It is correct that it is necessary to
achieve a big pool data in long term follow up to create the evidence about
utility of all these information in the clinical practice. But the only way
to achieve this goal is to apply slowly and seriously those state of the art
echocardiography powerful techniques in the clinical scenario.

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